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CRISPR CAR-T: Building Up the Immune System Against Cancer

Written by Evan MacLure '26

Edited by Jasmine Shum '24


Cancer continues to be the second leading cause of death worldwide, killing an average of 1,670 individuals everyday in 2022 [1]. Even with our advanced technology in chemotherapy and radiotherapy, we cannot establish a definitive cure for cancer which continues to rage inside the bodies of many.


Unfortunately, not only affecting adults, cancer is very prevalent among children with over 10,000 under the age of 15 being diagnosed each year in America [2]. An example is Johnny who was diagnosed with B-cell lymphoblastic leukemia, the most common childhood cancer, in 2012. He dealt with multiple rounds of chemotherapy to try and treat the cancer, but the treatment instead resulted in a severe fungal infection from a weakened immune system. The cancer remained and the chemotherapy proved to be ineffective [3]. So what to do?


For many years, chemotherapy was the golden drug for cancer, dating back all the way to the 1940s with the discovery of nitrogen mustard [4]. This drug was revolutionary, giving hope to millions suffering with cancers that were rapidly spreading to other parts of the body. By targeting a specific chemical reaction involved in DNA replication, chemotherapy essentially kills cancer cells all over the body. However, those are not the only cells. Chemotherapy damages many fast growing blood cells that are produced in the bone marrow, negatively affecting cell lines traveling to certain parts of the body [5]. This brings to perspective the tradeoffs of beneficial treatments.


That tradeoff does not have to be weighed with the development of more modern techniques in gene therapy. Enter CAR-T or Chimeric Antigen Receptor T cells. Instead of deteriorating one’s body with a drug that kills much more than just the target cells, weakening the immune system, CAR-T aims to improve treatment by strengthening the immune system with genetically modified T-cells [6]. T-cells are the body’s natural defense system, important in targeting pathogenic and infectious diseases including cancer and immune-regulating chronic disease. With its high involvement in one's immune response, T-cells were seen as an efficient life-saving alternative.


CAR-T cells are produced by each person’s cells within the body and are unique to every individual. It is essentially a personal living drug in the body that can multiply and attack with high specificity. The process involves removing some patient T-cells and then introducing a CAR viral vector, a package which introduces and attaches CAR receptors to each of the T-cells. Once these cells are established with the novel CAR biomarkers, T-cells are reintroduced into the patient’s body where they seek their prey of cancer cells through highly specific binding [6].


Flashback to 2013 in the hospital. With chemotherapy proving ineffective in treating the cancer, Johnny was able to receive CAR-T treatment as an alternative path focused on strengthening the immune system. Not only was the treatment effective, but it also completely eliminated the presence of cancer within his body, giving him the freedom to live the rest of his life without the looming shadow of disease [3].


An amped-up T-cell that can essentially cure cancer—this may sound a little too good to be true. Despite the recent hype around this new gene therapy approach, it still stands as a last resort after the usage of chemotherapy because of its incredibly expensive costs of $373,000 to well over $1 million as compared to chemotherapy which runs between around $10,000 and $200,000 [7][8]. With the incredible strain on our healthcare system from rising expenditures, it seems unreasonable and impossible to provide gene therapy to all patients. To bring more unfortunate news, the cells are only about 33% effective in providing complete remission from cancer while chemotherapy with radiotherapy can have equal if not higher rates [9]. The CAR-T cells are unable to consistently add CAR receptors and there are many scenarios of loss of potency and T-cell exhaustion [10]. So how can CAR be physically inserted into the domain to solve the issue of faulty cells? Enter CRISPR.


CRISPR CAS-9 has become known as a modern wonder in the medical and research field during the last decade, with its ability to genetically alter the human genome. Instead of introducing cells with a viral vector, a CAS-9 molecule, essentially a cut and paste tool, is added to insert CAR receptors directly into the genome of the T-cell with high precisions. Additionally, CRISPR can remove a PD-1 receptor domain that prevents the inhibition of T-cells to enhance cancer cell interaction [11]. The T-cells have received a little upgrade.


However, there still remain concerns on this topic with regard to the genome. CRISPR is still a new area of research with lots of unknowns on the effects to the body. Can the inserted genes affect other normal processes? Will some deleted genes change human behavior and cause fatal mutations? These questions are largely unanswered and growing in quantity as the technology continues to grow on the minds of many researchers. However, some encouraging insight has been introduced in a recent study. Patients with advanced refractory cancers received the NY-ESO-01 cancer targeting transgene inserted into the T-cells by CAS-9 to recognize cancer cells and provide clinical data. The results were very positive with few side effects encouraging the future of gene therapy [12]. Unfortunately, the drawback of CRISPR as with many forms of gene therapies is the unknown consequences and exorbitant costs, often exceeding one million dollars. There is still lots of work to be done if CRISPR is ever to enter the mainstream.


Despite the drawbacks, with these more modern forms of gene therapy coming to the table, patients like Johnny are able to have alternative forms of treatment. With great hype and research surrounding NY-ESO-01 and subsequent trials, there is hope for a more effective CRISPR CAR-T treatment to provide an alternative to chemotherapy. Gene therapy is proving effective in prolonging life, and since the body has a built in immune system, the question is utilization.

 

References

[1] ACS Medical Content and News Staff. 2022 cancer facts & figures cancer: Cancer death rate drops [Internet]. American Cancer Society. American Cancer Society; 2022 [cited 2022Nov13]. Available from: https://www.cancer.org/latest-news/facts-and-figures-2022.html


[2] Key statistics for childhood cancers [Internet]. American Cancer Society. [cited 2022Nov10]. Available from: https://www.cancer.org/cancer/cancer-in-children/key-statistics.html


[3] The Children's Hospital of Philadelphia. Car T-cell therapy for relapsed all: Johnny's story [Internet]. Children's Hospital of Philadelphia. The Children's Hospital of Philadelphia; 2022 [cited 2022Nov10]. Available from: https://www.chop.edu/stories/car-t-cell-therapy-relapsed-all-johnnys-story


[4] History of cancer treatments: Chemotherapy [Internet]. American Cancer Society. [cited 2022Nov10]. Available from: https://www.cancer.org/treatment/understanding-your-diagnosis/history-of-cancer/cancer-treatment-chemo.html


[5] What are the side effects of chemotherapy?: Official patient website [Internet]. COSELA (Trilaciclib) | What Are the Side Effects of Chemotherapy? [cited 2022Nov13]. Available from: https://www.cosela.com/patient/chemotherapy-and-your-bone-marrow


[6] Car T cells: Engineering immune cells to treat cancer [Internet]. National Cancer Institute. [cited 2022Nov10]. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells


[7] Aislinn Antrim AE. Study finds total cost of care for car-T, post-treatment events can exceed $1 million [Internet]. Pharmacy Times. Pharmacy Times; 2021 [cited 2022Nov10]. Available from: https://www.pharmacytimes.com/view/study-finds-total-cost-of-care-for-car-t-post-treatment-events-can-exceed-1-million


[8] Nunez K. Chemotherapy cost: What to know [Internet]. Healthline. Healthline Media; 2021 [cited 2022Nov10]. Available from: https://www.healthline.com/health/cancer/chemotherapy-cost


[9] Beer TC. CAR T-Cell Therapy: Frequently Asked Questions [Internet]. Lancaster General Health. Penn Medicine; 2022 [cited 2022Nov11]. Available from: https://www.lancastergeneralhealth.org/health-hub-home/2022/june/car-t-cell-therapy-frequently-asked-questions


[10] Dimitri A, Herbst F, Fraietta JA. Engineering the next-generation of car T-cells with CRISPR-Cas9 gene editing [Internet]. Molecular cancer. BioMed Central; 2022 [cited 2022Nov10]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932053/


[11]Roberts R. CRISPR CAR-T cells: Edited T Cells Are Revolutionizing Cancer Treatment [Internet]. Synthego. 2021 [cited 2022Nov10]. Available from: https://www.synthego.com/blog/car-t-crispr-cancer#what-you-need-to-know-about-crispr-and-car-t-cells


[12] Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL, Lancaster E, et al. CRISPR-engineered T cells in patients with refractory cancer. Science. 2020;367(6481).


IMAGE CITATION: https://www.the-scientist.com/news-opinion/ten-years-of-crispr-70171


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